This invention describes soluble, monovalent, non-natural protein molecules that can activate NK cells and certain T-cells to attack specific cellular target cells by attaching the NKG2D-binding portions of monovalent MICA or MICB protein, i.e. their a1-a2 platform domain, to the intended target cell specifically. The a1-a2 domain is contiguous with a heterologous a3 domain that has been genetically modified to bind directly or indirectly to the extracellular aspect of the target cell, thereby serving as the targeting domain. The genetic modification to create a non-natural and non-terminal targeting motif within the a3 domain can include a portion of an antibody, another protein molecule or portion thereof, a peptide, or a non-natural, modified a3 domain of a MIC protein.
